Papp-Wallace, Krisztina M.Mallo Cancela, SusanaBethel, Christopher R.Taracila, Magdalena A.Hujer, Andrea M.Viña Fernández, Anabel MaríaGatta, Julian A.Smith, Kerri M.Xu, YanPage, Malcolm G.P.Desarbre, EricBou, GermánBonomo, Robert2026-09-042026-09-042013-11-13Papp-Wallace KM, Mallo S, Bethel CR, Taracila MA, Hujer AM, Fernández A, Gatta JA, Smith KM, Xu Y, Page MG, Desarbre E, Bou G, Bonomo RA. A kinetic analysis of the inhibition of FOX-4 β-lactamase, a plasmid-mediated AmpC cephalosporinase, by monocyclic β-lactams and carbapenems. J Antimicrob Chemother. 2014 Mar;69(3):682-90.0305-7453https://hdl.handle.net/2183/49152[Abstract] Objectives: Class C β-lactamases are prevalent among Enterobacteriaceae; however, these enzymes are resistant to inactivation by commercially available β-lactamase inhibitors. In order to find novel scaffolds to inhibit class C β-lactamases, the comparative efficacy of monocyclic β-lactam antibiotics (aztreonam and the siderophore monosulfactam BAL30072), the bridged monobactam β-lactamase inhibitor BAL29880, and carbapenems (imipenem, meropenem, doripenem and ertapenem) were tested in kinetic assays against FOX-4, a plasmid-mediated class C β-lactamase (pmAmpC). Methods: The FOX-4 β-lactamase was purified. Steady-state kinetics, electrospray ionization mass spectrometry (ESI-MS) and ultraviolet difference (UVD) spectroscopy were conducted using the β-lactam scaffolds described. Results: The K(i) values for the monocyclic β-lactams against FOX-4 β-lactamase were 0.04 ± 0.01 μM (aztreonam) and 0.66 ± 0.03 μM (BAL30072), and the Ki value for the bridged monobactam BAL29880 was 8.9 ± 0.5 μM. For carbapenems, the Ki values ranged from 0.27 ± 0.05 μM (ertapenem) to 2.3 ± 0.3 μM (imipenem). ESI-MS demonstrated the formation of stable covalent adducts when the monocyclic β-lactams and carbapenems were reacted with FOX-4 β-lactamase. UVD spectroscopy suggested the appearance of different chromophoric intermediates. Conclusions: Monocyclic β-lactam and carbapenem antibiotics are effective mechanism-based inhibitors of FOX-4 β-lactamase, a clinically important pmAmpC, and provide stimulus for the development of new inhibitors to inactivate plasmidic and chromosomal class C β-lactamases.engThis is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record is available online on the OUP website.Bridged monobactamsCarbapenemsMonosulfactamβ-lactamase inhibitorsjournal articleopen access10.1093/JAC/DKT434